Robert L Coleman1, Gini F Fleming1, Mark F Brady1, Elizabeth M Swisher1, Karina D Steffensen1, Michael Friedlander1, Aikou Okamoto1, Kathleen N Moore1, Noa Efrat Ben-Baruch1, Theresa L Werner1, Noelle G Cloven1, Ana Oaknin1, Paul A DiSilvestro1, Mark A Morgan1, Joo-Hyun Nam1, Charles A Leath1, Shibani Nicum1, Andrea R Hagemann1, Ramey D Littell1, David Cella1, Sally Baron-Hay1, Jesus Garcia-Donas1, Mika Mizuno1, Katherine Bell-McGuinn1, Danielle M Sullivan1, Bruce A Bach1, Sudipta Bhattacharya1, Christine K Ratajczak1, Peter J Ansell1, Minh H Dinh1, Carol Aghajanian1, Michael A Bookman1. 1. From the University of Texas M.D. Anderson Cancer Center, Houston (R.L.C.); University of Chicago Medicine (G.F.F.) and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University (D.C.), Chicago, and AbbVie, North Chicago (D.M.S., B.A.B., S.B., C.K.R., P.J.A., M.H.D.) - all in Illinois; NRG Oncology Statistical and Data Center, Roswell Park Cancer Institute, Buffalo (M.F.B.), and Memorial Sloan Kettering Cancer Center, New York (K.B.-M., C.A.) - both in New York; University of Washington-Seattle Cancer Care Alliance, Seattle (E.M.S.); Lillebaelt University Hospital of Southern Denmark, Vejle, and the University of Southern Denmark, Odense (K.D.S.); Prince of Wales Clinical School, University of New South Wales and Royal Hospital for Women (M.F.), and the Northern Cancer Institute (S.B.-H.), Sydney; Jikei University School of Medicine, Tokyo (A. Okamoto), and Aichi Cancer Center Hospital, Nagoya (M.M.) - both in Japan; Stephenson Cancer Center at the University of Oklahoma Health Sciences Center, Oklahoma City (K.N.M.); Kaplan Medical Center, Rehovot, Israel (N.E.B.-B.); Huntsman Cancer Institute, University of Utah, Salt Lake City (T.L.W.); Texas Oncology, U.S. Oncology Research Network, Fort Worth (N.G.C.); Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona (A. Oaknin); Women and Infants Hospital, Providence, RI (P.A.D.); Penn Medicine, Philadelphia (M.A.M.); University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea (J.-H.N.); O'Neal Comprehensive Cancer Center at the University of Alabama at Birmingham, Birmingham (C.A.L.); Oxford University Hospitals, Oxford, United Kingdom (S.N.); Washington University School of Medicine, St. Louis (A.R.H.); Kaiser Permanente Northern California, San Francisco (R.D.L., M.A.B.); and H.M. Hospitales-Centro Integral Oncológico H.M. Clara Campal, Madrid (J.G.-D.).
Abstract
BACKGROUND: Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma. METHODS: In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the veliparib-throughout group as compared with the control group, analyzed sequentially in the BRCA-mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the BRCA-mutation cohort), and the intention-to-treat population. RESULTS: A total of 1140 patients underwent randomization. In the BRCA-mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P<0.001); in the HRD cohort, it was 31.9 months and 20.5 months, respectively (hazard ratio, 0.57; 95 CI, 0.43 to 0.76; P<0.001); and in the intention-to-treat population, it was 23.5 months and 17.3 months (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). Veliparib led to a higher incidence of anemia and thrombocytopenia when combined with chemotherapy as well as of nausea and fatigue overall. CONCLUSIONS: Across all trial populations, a regimen of carboplatin, paclitaxel, and veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer progression-free survival than carboplatin plus paclitaxel induction therapy alone. The independent value of adding veliparib during induction therapy without veliparib maintenance was less clear. (Funded by AbbVie; VELIA/GOG-3005 ClinicalTrials.gov number, NCT02470585.).
RCT Entities:
BACKGROUND: Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma. METHODS: In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the veliparib-throughout group as compared with the control group, analyzed sequentially in the BRCA-mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the BRCA-mutation cohort), and the intention-to-treat population. RESULTS: A total of 1140 patients underwent randomization. In the BRCA-mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P<0.001); in the HRD cohort, it was 31.9 months and 20.5 months, respectively (hazard ratio, 0.57; 95 CI, 0.43 to 0.76; P<0.001); and in the intention-to-treat population, it was 23.5 months and 17.3 months (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). Veliparib led to a higher incidence of anemia and thrombocytopenia when combined with chemotherapy as well as of nausea and fatigue overall. CONCLUSIONS: Across all trial populations, a regimen of carboplatin, paclitaxel, and veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer progression-free survival than carboplatin plus paclitaxel induction therapy alone. The independent value of adding veliparib during induction therapy without veliparib maintenance was less clear. (Funded by AbbVie; VELIA/GOG-3005 ClinicalTrials.gov number, NCT02470585.).
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